# Development of a Peptide-Drug Conjugate for Topically Treating the Viral Skin Disease Molluscum Contagiosum

> **NIH NIH R41** · FOX CHASE CHEMICAL DIVERSITY CENTER, INC · 2021 · $306,500

## Abstract

ABSTRACT
Molluscum contagiosum (MC) is a highly contagious skin disease caused by the poxvirus, MCV. It
remains an Unmet Medical Need due to lack of an approved antiviral drug. MC appears as lesions on
the body and face that can last months-years before resolving. Lesions occur most frequently in children
(5%) and immune compromised individuals (5-18%). The infection is confined to the epidermal skin layers;
it is not systemic. Transmission spreads directly from person-person contact, autoinoculation or indirect
contact with fomites. Current treatments can be painful, cause scarring, and psychological distress. None of
the current treatments that include a range of physical, chemical and medicinal interventions are uniformly
accepted or FDA approved. The reason why no approved drug against MCV has been developed is
because the virus cannot be grown in tissue culture for testing. We have now made four major
breakthroughs: First, we have identified a protein target (mD4) of MCV that is essential for
replication. The mD4 protein functions as a processivity factor (PF) that tethers the viral Polymerase (Pol)
to the template to enable continuous synthesis of DNA. Second, we have constructed a mD4-
surrogate virus (mD4-VV), providing the first cell-based system for screening compounds against an
essential MCV target protein (mD4) in infected cells. Third, we have synthesized a small molecule
(7269) that that binds a precise region of the mD4 target protein, causing it to unfold and no longer
function. While 7269 can block infection by the surrogate virus, we were unable to improve its potency or
eliminate its slight toxicity despite an intense medicinal chemistry campaign. Fourth, we overcame this
impasse by conjugating a peptide to produce TriValine-7269 that binds the mD4 with a potency that is
6.3-fold greater than that of unconjugated 7269 and has no measurable toxicity. Since TriValine-7269
does not alter direct binding to the mD4 target, its increased potency is due to cellular penetration and/or
stability. The challenge that impedes further drug development is that TriValine-7269 has no related
analog of equal or greater potency to mitigate risk in the next stages of drug development. The GOAL is to
identify analogs of TriValine-7269 of equal or greater potency as essential backups. AIM 1 will utilize
medicinal chemistry to synthesize analogs of TriValine-7269. The focus will be to vary both the Peptide
and Linker portions of TriValine-7269. The 7269 portion will not be modified since it has already been
optimized. We will produce 30-40 analogs. AIM 2 will evaluate new analogs for antiviral potency against
the surrogate virus; cytotoxicity; blocking in vitro processive DNA synthesis; binding to the mD4 target.
AIM 3 will evaluate structurally distinct analogs for in vitro ADME activities that are relevant for topical
application including metabolic stability, solubility and cell permeability. Conjugates with criteria that
exceed or match TriVali...

## Key facts

- **NIH application ID:** 10257353
- **Project number:** 1R41AI162385-01
- **Recipient organization:** FOX CHASE CHEMICAL DIVERSITY CENTER, INC
- **Principal Investigator:** ROBERT Paul RICCIARDI
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $306,500
- **Award type:** 1
- **Project period:** 2021-04-19 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10257353

## Citation

> US National Institutes of Health, RePORTER application 10257353, Development of a Peptide-Drug Conjugate for Topically Treating the Viral Skin Disease Molluscum Contagiosum (1R41AI162385-01). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10257353. Licensed CC0.

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